Synthesis, Biological Evaluation and Principal Component Analysis of Arylidene Analogues of Barbituric Acid Obtained via Knoevenagel Condensation

Cardoso, Bruce S.; Lima, Juliana G. M.; Ribeiro, Luciano; Corrêa, José R.; Ramos, Luciana M.

doi:10.21577/0103-5053.20250057

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Full Paper • J. Braz. Chem. Soc. 36 (7) • 2025 • https://doi.org/10.21577/0103-5053.20250057 linkcopy

Synthesis, Biological Evaluation and Principal Component Analysis of Arylidene Analogues of Barbituric Acid Obtained via Knoevenagel Condensation

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

The synthesis of 5-arylidene barbiturates has been extensively documented through various methodologies. In this study, we synthesized ten derivatives of barbiturate 5-arylidenes using an optimized Knoevenagel reaction catalyzed by a synthetic enzyme supported in chloride ionic liquids, achieving satisfactory yields ranging from 68 to 97%. Upon evaluating the biological properties of these ten compounds, derivative 12 (5-(2-hydroxy)benzylidene of acid barbituric), a nitro compound, exhibited broad-spectrum bactericidal activity against both the Gram-negative bacterium Escherichia coli and the Gram-positive bacillus Bacillus subtilis. Furthermore, it demonstrated moderate fungistatic activity against Candida albicans. Additionally, derivatives 10 (5-benzylidene of acid barbituric) and 11 (5-(3-nitro) benzylidene of acid barbituric) displayed antioxidant activity comparable to that of the positive control quercetin, albeit only at the highest concentration tested (400 µg mL^-1). This study integrates quantum chemistry calculations with multivariate statistical methods, specifically principal component analysis, to correlate theoretical descriptors with the antibacterial and fungicidal activities of the compounds. In conclusion, given the promising outcomes of this investigation and recognizing the scarcity of studies delving into the biological properties of 5-arylidene barbiturate compounds, it is suggested that future research should explore other biological and pharmacological aspects of these compounds.

Keywords:
catalysis; polietilenoamine; ionic liquids; antibacterial; SAR; quantum chemistry calculations

entry	Catalyst	Solvent	time / h	Temperature / °C	Yield / %
1	-	water	2	80	15
2	FeCl₃	water	2	80	75
3	CuCl₂	water	2	80	69
4	MAI.Fe₂Cl₇^a	water	2	80	79
5	MSI^b	water	2	80	71
6	SnCl₂.2H₂O	water	2	80	85
7	p-TSOH	water	2	80	79
8	PEI.IL^c	water	2	80	87
9	PEI.IL^c	ethanol	2	80	81
10	PEI.IL^c	methanol	2	80	77
11	PEI.IL^c	toluene	2	80	70
12	PEI.IL^c	1,4-dioxane	2	80	55
13	PEI.IL^c	hexane	2	80	69
14	PEI.IL^c	THF	2	80	70
15	PEI.IL^c	acetonitrile	2	80	52
16	PEI.IL^c	water	1	80	40
17	PEI.IL^c	water	4	80	97
18	PEI.IL^c	water	6	80	43
19	PEI.IL^c	water	24	80	43
20	PEI.IL^c	water	4	rt	76
21	PEI.IL^c	water	4	60	75
22	PEI.IL^c	water	4	90	69
23	PEI.IL^c	water	4	100	59

Compound	Bacillus subtilis (ATCC 6633)		Escherichia coli (ATCC 25312)
Compound	MIC / (mg mL^-1)	MBC / (mg mL^-1)	MIC / (mg mL^-1)	MBC / (mg mL^-1)
10	≥ 500	≥ 1000	≥ 1000	≥ 2000
11	≥ 500	≥ 2000	≥ 250	≥ 1000
12	≥ 31.25	≥ 250	≥ 125	≥ 2000
13	≥ 500	≥ 2000	≥ 250	≥ 1000
14	≥ 250	≥ 2000	≥ 500	≥ 500
15	≥ 1000	≥ 2000	≥ 2000	≥ 2000
16	≥ 2000	≥ 2000	≥ 2000	≥ 2000
17	≥ 500	≥ 2000	≥ 500	≥ 500
18	≥ 2000	≥ 2000	≥ 500	≥ 2000
19	≥ 2000	≥ 2000	≥ 2000	≥ 2000

Compound	Candida albicans (ATCC 10231)
Compound	MIC / (mg mL^-1)	MFC / (mg mL^-1)
10	≥ 500	≥ 2000
11	≥ 1000	≥ 2000
12	≥ 500	≥ 2000
13	≥ 2000	≥ 2000
14	≥ 1000	≥ 2000
15	≥ 2000	≥ 2000
16	≥ 2000	≥ 2000
17	≥ 2000	≥ 2000
18	≥ 2000	≥ 2000
19	≥ 2000	≥ 2000

Compound	Activity	E_HOMO / Hartree	GAP / Hartree
10	active	-8.556	7.025
11	active	-9.190	7.283
12	active	-9.261	7.462
13	active	-8.503	7.253
14	active	-8.210	6.872
15	inactive	-7.926	6.131
16	inactive	-7.981	6.754
17	active	-8.289	6.822
18	inactive	-7.1032	5.635
19	inactive	-7.810	6.275

	E_HOMO	GAP
E_HOMO	1	-0.9315
GAP	-0.9315	1

Compound	Activity	Charge 22 / e	B.O. 22	A(9,8,19) / degree
10	active	0.1025	0.9239	111.41
11	inactive	0.1530	0.9025	111.48
12	active	0.7043	0.8978	111.44
13	inactive	-0.1151	1.0750	111.48
14	inactive	0.1492	0.9239	111.43
15	inactive	-0.4034	1.0306	111.51
16	inactive	-0.5169	1.0381	111.56
17	inactive	-0.2650	1.0345	111.46
18	inactive	-0.2595	1.1780	111.62
19	inactive	-0.4111	1.0042	111.49

	Charge 22	B.O.22	A (9,8,19)
Charge 22	1	0.6809	-0.5945
B.O. 22	-0.6809	1	0.8117
A (9,8,19)	-0.5945	0.8117	1

Compound	Activity	E_LUMO / Hartree	B.O. 22	B.O. 17
10	inactive	0.4823	-0.0508	-0.7301
11	active	2.0663	-0.7302	0.4070
12	active	1.3039	-0.8687	-0.4026
13	inactive	-1.1168	0.9215	0.1388
14	active	1.4659	1.7858	0.3308
15	inactive	0.1443	-1.0386	0.5280
16	inactive	-0.7946	1.0967	-0.1112
17	inactive	-0.7848	-0.1386	-0.2393
18	inactive	-2.5206	-0.7693	0.2756
19	inactive	-0.2459	-0.2076	-0.1968

	E_LUMO / Hartree	B.O. 22	B.O. 17
E_LUMO / Hartree	1	0.4597	0.0917
B.O. 22	0.4597	1	0.7474
B.O. 17	0.0917	0.8117	1

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